Cytosolic phospholipase A2 (cPLA2), cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) regulate the formation of physiologically active prostaglandins, the production of which is known to be elevated in several renal disorders. We studied the relevance of these enzymes in polycystic kidney disease (PKD) by using two models of the disease: a model in which decline in renal function begins in adulthood (CD1-pcy/pcy mouse) and one in which it occurs early, during growth (Han:SPRD-cy rat). Immunoblotting analyses of cytosolic and particulate kidney fractions revealed that cPLA2 levels are significantly higher (by 34-131%) in the latter stages of the disease in both models. Renal COX enzymes were found only in the particulate fractions, with COX-1 87% higher in 6-month-old CD1-pcy/pcy mice compared with normal controls, and 110% higher in male 70-day-old Han:SPRD-cy rats with cystic kidneys compared with controls. Renal COX-2 was detected only in the rats and was 58% lower in diseased kidneys of 70-day-old male Han:SPRD-cy rats, indicating that cPLA2 is coupled to COX-1 in the kidney. The altered levels of these eicosanoid-regulating enzymes has implications for the use of NSAIDS and specific COX inhibitors in individuals with this disorder.